Topotecan hydrochloride is (10-[(dimethyl amino) methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)dione hydrochloride) a compound of formula (I).

Topotecan is a semi-synthetic analogue of camptothecin, an agent derived from the Oriental yew tree, Camptothecan accuminata. The cytotoxic effects of the camptothecins are believed to be related to their activity as inhibitors of topoisomerase-I, an enzyme involved in the replication and repair of nuclear DNA. As DNA is replicated in dividing cells, topoisomerase-I acts by binding to super-coiled DNA and causing single-stranded breaks in that DNA. As a result, topoisomerase-I is able to relieve the torsional stresses that are introduced into DNA ahead of the replication complex or moving replication fork. Topotecan inhibits topoisomerase-I by stabilizing the covalent complex of enzyme and strand-cleaved DNA, which is an intermediate of the catalytic mechanism, thereby inducing breaks in the protein-associated DNA single-strands, resulting in cell death. Topotecan hydrochloride stops the growth of cancer cells by preventing the development of elements necessary for cell division.
U.S. Pat. No. 5,004,758 discloses water soluble Camptothecin analogs, which includes topotecan (9-dimethylamino methyl-10-hydroxy camptothecin), preferably (S)-topotecan and its Hydrochloride salt.
U.S. Pat. No. 5,734,056 disclose Camptothecin analogs (which include topotecan) and a process for the preparation of such analogs and its intermediates.
U.S. Pat. No. 5,155,225 describes processes for making Pyrano[3′,4′:6,7]indolizino-[1,2-B]quinolinones.
WO2005046608 discloses a novel crystalline form of topotecan monohydrochloride pentahydrate, corresponding pharmaceutical compositions, methods of preparation and use for anti-viral and other cancer-related diseases.
The present invention relates to the solid state physical properties of topotecan hydrochloride. These properties can be influenced by controlling the conditions under which topotecan hydrochloride is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's body fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
Topotecan hydrochloride exhibits polymorphism. Polymorphism is the property of some molecules to adopt more than one crystalline form in the solid state. A single molecule can give rise to a variety of crystalline solids having distinct physical properties that can be measured in a laboratory like its thermal behaviour, e.g. melting point and differential scanning calorimetry (DSC) thermogram, dissolution rate, flowability, X-ray diffraction pattern, infrared absorption spectrum and NMR spectrum.
The differences in the physical properties of polymorphs result from the conformation, orientation and intermolecular interactions of adjacent molecules in the crystalline solid. Rate of dissolution of a pharmaceutical compound depends upon its stable crystalline form. The rate of dissolution can have increased effect on the therapeutic efficacy of the administered drug. Hence, this property of the pharmaceutical compound is considered as an important feature in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Thus, it is clear from the foregoing discussion, it would be desirable to have active pharmaceutical ingredient in a stable crystalline form having improved bulk handling and dissolution properties and this becomes the object of the present invention.